Amino acids are often employed as raw materials in the preparation, by a sequence of reactions, of compounds having various uses. In many of these sequences it is necessary to reversibly block a primary amino group of the amino acid or its salts in order that the blocked compound may undergo further reactions which would otherwise irrevocably destroy the amino group, and yet permit later regeneration of the primary amino group.
Benzyloxycarbonyl is eminently suited as the blocking group for these purposes. See for example, U.S. Pat. No. 4,293,706, Floyd et al, "Monobactams . . . ", Journal of Organic Chemistry, Vol. 47, No. 1, pages 176-178 (1982), Cimarusti et al, "Monobactams . . . ", Journal of Organic Chemistry, Vol. 47, pages 179-180 (1982), and Wertheim, Textbook of Organic Chemistry, 3d edition, pages 808-809 (1951), the entire disclosures of which are incorporated herein by reference. The benzyloxycarbonyl group may be introduced by reacting alkali metal salt of the amino acid with a benzylhaloformate, such as benzylchloroformate or benzylbromoformate, in a polyphase reaction mixture.
When the amino acid contains, in addition to a primary amino group and at least one carboxylate anion, at least one functional group selected from the class consisting of hydroxyl, additional primary amino, secondary amino, primary imido, and primary amido, product yields are reduced due to the undesired side reaction of the benzylhaloformate with the additional functionality. A hydroxyl group, for instance, can and often does react with the benzylhaloformate to form an undesired carbonate. It is important to observe that loss of product by this mechanism pertains only to those amino acids containing the additional functionality; it does not pertain to those amino acids which do not contain the additional functionality.
Poly(oxyalkylene) glycols and polymer-supported poly(oxyalkylene) alcohols are known phase-transfer reagents which have been employed for various reactions. See, for example, Kimura and Regen, "Poly(ethylene glycols) and Poly(ethylene glycol)-Grafted Copolymers . . . ", Journal of Organic Chemistry, Volume 48, No. 2, pages 195-198 (1983); Gokel, Goli, and Schultz, "Binding Profiles for Oligoethylene Glycols . . . ", Journal of Organic Chemistry, Volume 48, No. 17, pages 2837-2842 (1983); Kimura and Regen, "Poly(ethylene glycols) Are Extraordinary Catalysts in Liquid-Liquid Two-Phase Dehydrohalogenation", Journal of Organic Chemistry, Volume 47, No. 12, pages 2493-2494 (1982); Szabo, Aranyosi, and Toke, "Polyethylene Glycol Derivatives As Complexing Agents and Phase-Transfer Catalysts, IV" Acta Chemica Scientiarum Hungaricae, Volume 110, pages 215-224 (1982); Sawicki, "Phase Transfer Catalysts. Polyethylene Glycols Immobilized onto Metal Oxide Surfaces", Tetrahedron Letters Volume 23, No. 22, pages 2249-2252 (1982); Heffernan, MacKenzie, and Sherrington, "Non-supported and Resin-supported Oligo (oxyethylenes) as Solid-Liquid Phase-transfer Catalysts. Effect of Chain Length and Head-group.", J.C.S. Perkin Transactions II, pp 514-517 (1981); Zupancic and Kokalj, "Aromatic .alpha.,.beta.-Unsaturated Nitriles via Polyethylene Glycol-Catalyzed Two-Phase Aldol-Type Condensation", Synthesis, November 1981, pages 913-915; Regen, Besse, and McLick, "Solid-Phase Cosolvents . . . ", Journal of the American Chemical Society, Volume 101, No. 1, pages 116-120 (1979); and Balasubramanian, Sukumar, and Chandani, "Linear Unsubstituted Polyethylene Glycols as Phase Transfer Catalysts", Tetrahedron Letters, No. 37, pages 3543-3544 (1979), the entire disclosures of which are incorporated herein by reference. Neither the poly(oxyalkylene) glycols nor the polymer-supported poly(oxyalkylene) alcohols have, however, been employed as phase-transfer reagents in blocking a primary amino group of an amino acid having the additional functionality discussed above.